Original Article

Possible Role of the Pineal Gland in the Human Memory System

Abstract

Purpose: Pineal Gland (PG) is a midline brain structure and part of the epithalamus, a dorsal posterior segment of the diencephalon. Most findings on the role of this structure in brain function are relevant to melatonin secretion, and only a few reports are available on its involvement in brain cognition.

Materials and Methods: Due to some suggestions on the role of the diencephalon areas, including the PG, in the human memory system, we used data from two previous MRI studies on 32 and 295 healthy individuals, in order to identify first, if the PG shows activations in fMRI and during a memory retrieval task as well as showing functional connectivity with other brain structures, and second, if there are any associations between the PG volume and the memory scores of the individuals.

Results: Using a standard PG atlas, our results showed significant activations in PG during memory retrieval, with the strength of these activations increasing with the increment of the cognitive load of the task. Also, PG showed functional connectivity with other brain structures during fMRI, the pattern of which also changed with the cognitive load of the retrieval. Finally, the volume of the PG showed significant associations with the scores of the memory tests.

Conclusion: Our knowledge of the PG still needs improvement, and we hope our findings here could be a help for that as well as a help to better understand the mechanisms of memory storage and retrieval in humans.

[1] Razavi F, Raminfard S, Kalantar H, et al. A probabilistic atlas of the pineal gland in the standard space. Front Neuroinform 2021; 15: 19.
[2] Hikosaka O. The habenula: from stress evasion to value-based decision-making. Nat Rev Neurosci 2010; 11: 503–513.
[3] Nölte I, Lütkhoff A-T, Stuck BA, et al. Pineal volume and circadian melatonin profile in healthy volunteers: An interdisciplinary approach. J Magn Reson Imaging 2009; 30: 499–505.
[4] Sisakhti M, Shafaghi L, Batouli SAH. The Volumetric Changes of the Pineal Gland with Age: An Atlas-based Structural Analysis. Exp Aging Res 2022; 1–31.
[5] Park J, Han JW, Lee JR, et al. Lifetime coffee consumption, pineal gland volume, and sleep quality in late life. Sleep; 41. Epub ahead of print 14 July 2018. DOI: 10.1093/sleep/zsy127.
[6] Sigurdardottir LG, Markt SC, Sigurdsson S, et al. Pineal Gland Volume Assessed by MRI and Its Correlation with 6-Sulfatoxymelatonin Levels among Older Men. J Biol Rhythms 2016; 31: 461–469.
[7] Beker-Acay M, Turamanlar O, Horata E, et al. Assessment of Pineal Gland Volume and Calcification in Healthy Subjects: Is it Related to Aging? J Belgian Soc Radiol 2016; 100: 1–7.
[8] Sun B, Wang D, Tang Y, et al. The pineal volume: a three-dimensional volumetric study in healthy young adults using 3.0T MR data. Int J Dev Neurosci 2009; 27: 655–660.
[9] Hasegawa A, Ohtsubo K, Mori W. Pineal gland in old age; quantitative and qualitative morphological study of 168 human autopsy cases. Brain Res 1987; 409: 343–349.
[10] Raghuprasad MS, Manivannan M. Volumetric and Morphometric Analysis of Pineal and Pituitary Glands of an Indian Inedial Subject. Ann Neurosci 2018; 25: 279–288.
[11] Al-Holou WN, Maher CO, Muraszko KM, et al. The natural history of pineal cysts in children and young adults. J Neurosurg Pediatr PED 2010; 5: 162–166.
[12] Silman. RE, Leone RM, Hooper RJL, et al. Melatonin, the pineal gland and human puberty. Nature 1979; 282: 301–303.
[13] Goldman B, Gwinner E, Karsch FJ, et al. Chronobiology: biological timekeeping. Circannual Rhythm Photoperiod 2004; 107–142.
[14] Cajochen C, Kräuchi K, Wirz-Justice A. Role of Melatonin in the Regulation of Human Circadian Rhythms and Sleep. J Neuroendocrinol 2003; 15: 432–437.
[15] Golan J, Torres K, Staśkiewicz G, et al. Morphometric parameters of the human pineal gland in relation to age, body weight and height. Folia Morphol (Warsz) 2002; 61: 111–113.
[16] Reyes PF. Age related histologic changes in the human pineal gland. Prog Clin Biol Res 1982; 92: 253–61.
[17] Reiter R, Tan D-X, Korkmaz A, et al. Light at Night, Chronodisruption, Melatonin Suppression, and Cancer Risk: A Review. Crit Rev Oncog 2007; 13: 303–328.
[18] Sarrazin S, Etain B, Vederine F-E, et al. MRI exploration of pineal volume in bipolar disorder. J Affect Disord 2011; 135: 377–379.
[19] Nishida S. Metabolic effects of melatonin on odative stress and dbetes mellitus. Endocrine 2005; 27: 131–135.
[20] Sparks DL, Hunsaker III JC. The Pineal Gland in Sudden Infant Death Syndrome: Preliminary Observations. J Pineal Res 1988; 5: 111–118.
[21] Bumb JM, Schilling C, Enning F, et al. Pineal gland volume in primary insomnia and healthy controls: a magnetic resonance imaging study. J Sleep Res 2014; 23: 276–282.
[22] Fındıklı E, Inci M, Gökçe M, et al. Pineal gland volume in schizophrenia and mood disorders. Psychiatr Danub 2015; 27: 153–158.
[23] Matsuoka T, Imai A, Fujimoto H, et al. Reduced Pineal Volume in Alzheimer Disease: A Retrospective Cross-sectional MR Imaging Study. Radiology 2017; 286: 170188.
[24] Grosshans M, Vollmert C, Vollstädt-Klein S, et al. The association of pineal gland volume and body mass in obese and normal weight individuals: A pilot study. Psychiatr Danub 2016; 28: 220–224.
[25] Atmaca M, Korucu T, Caglar Kilic M, et al. Pineal gland volumes are changed in patients with obsessive-compulsive personality disorder. J Clin Neurosci 2019; 70: 221–225.
[26] Mahlberg R, Kienast T, Hädel S, et al. Degree of pineal calcification (DOC) is associated with polysomnographic sleep measures in primary insomnia patients. Sleep Med 2009; 10: 439–445.
[27] López-Muñoz F, Molina JD, Rubio G, et al. An historical view of the pineal gland and mental disorders. J Clin Neurosci 2011; 18: 1028–1037.
[28] Liou C-H, Hsieh C, Hsieh C-H, et al. Correlation between Pineal Activation and Religious Meditation Observed by Functional Magnetic Resonance Imaging. Nat Preced; 2. Epub ahead of print 15 November 2007. DOI: 10.1038/npre.2007.1328.1.
[29] Batouli SAH, Sisakhti M. Investigating A Hypothesis on The Mechanism of Long-Term Memory Storage. NeuroQuantology; 17. Epub ahead of print 28 March 2019. DOI: 10.14704/nq.2019.17.3.1813.
[30] Batouli SAH, Sisakhti M, Haghshenas S, et al. Iranian Brain Imaging Database: A Neuropsychiatric Database of Healthy Brain. BCN 2021; 12: 115–132.
[31] Sisakhti M, Sachdev PS, Batouli SAH. The Effect of Cognitive Load on the Retrieval of Long-Term Memory: An fMRI Study . Frontiers in Human Neuroscience 2021; 15: 606.
[32] Batouli SAH. Seven ambiguities in explaining the human memory system in the Principles of Neural Science book. Basic Clin Neurosci 2022; In Press.
[33] Batouli SAH. Seven Ambiguities in Explaining the Human Memory System in the Principles of Neural Science Book. Preprints; 2021040060. Epub ahead of print 2021. DOI: 10.20944/preprints202104.0060.v1.
[34] Vann SD, Nelson AJD. Chapter 9 - The mammillary bodies and memory: more than a hippocampal relay. In: O’Mara S, Tsanov MBT-P in BR (eds) The Connected Hippocampus. Elsevier, pp. 163–185.
[35] Sanders D, Simkiss D, Braddy D, et al. Nicotinic receptors in the habenula: importance for memory. Neuroscience 2010; 166: 386–390.
[36] Lecourtier L, Neijt HC, Kelly PH. Habenula lesions cause impaired cognitive performance in rats: implications for schizophrenia. Eur J Neurosci 2004; 19: 2551–2560.
[37] Sharma M, Madhugiri V, Nanda A. James L. Poppen and Surgery of the “Seat of the Soul”: A Contemporary Perspective. World Neurosurg 2014; 82: 529–534.
[38] Batouli SAH, Sisakhti M. Some Points to Consider in a Task-Based fMRI Study: A Guideline for Beginners. Front Biomed Technol; 7. Epub ahead of print 30 March 2020. DOI: 10.18502/fbt.v7i1.2725.
[39] Henry JD, Crawford JR. The short‐form version of the Depression Anxiety Stress Scales (DASS‐21): Construct validity and normative data in a large non‐clinical sample. Br J Clin Psychol 2005; 44: 227–239.
[40] Sahebi A, Asghari MJ, Salari RS. Validation of Depression Anxiety and Stress Scale (DASS-21) for an Iranian Population. J Iran Psychol 2005; 1: 36–54.
[41] Mitrushina M, Satz P, Chervinsky A, et al. Performance of four age groups of normal elderly on the Rey Auditory‐Verbal Learning Test. J Clin Psychol 1991; 47: 351–357.
[42] Ferreira Correia A, Campagna Osorio I. The Rey auditory verbal learning test: normative data developed for the venezuelan population. Arch Clin Neuropsychol 2013; 29: 206–215.
[43] Rezvanfard M, Ekhtiari H, Noroozian M. The Rey Auditory Verbal Learning Test: alternate forms equivalency and reliability for the Iranian adult population (Persian version). Arch Iran Med 2011; 14: 104.
[44] Possin KL, Laluz VR, Alcantar OZ, et al. Distinct neuroanatomical substrates and cognitive mechanisms of figure copy performance in Alzheimer’s disease and behavioral variant frontotemporal dementia. Neuropsychologia 2011; 49: 43–48.
[45] Rosselli M, Loewenstein DA, Curiel RE, et al. Effects of Bilingualism on Verbal and Nonverbal Memory Measures in Mild Cognitive Impairment. J Int Neuropsychol Soc 2019; 25: 15–28.
[46] Wechsler D. Wechsler memory scale-revised. Psychol Corp.
[47] Hester RL, Kinsella GJ, Ong BEN. Effect of age on forward and backward span tasks. J Int Neuropsychol Soc 2004; 10: 475–481.
[48] Kane MJ, Conway ARA, Miura TK, et al. Working memory, attention control, and the N-back task: a question of construct validity. J Exp Psychol Learn Mem Cogn 2007; 33: 615.
[49] Mirdehghan M, Nejati V, Ganjian G. Working Memory in regard to Persian and Chinese words for Persian Learners of Chinese. mdrsjrns 2016; 7: 197–213.
[50] Smith SM. Fast robust automated brain extraction. Hum Brain Mapp 2002; 17: 143–155.
[51] Fonov V, Evans AC, Botteron K, et al. Unbiased average age-appropriate atlases for pediatric studies. Neuroimage 2011; 54: 313–327.
[52] Sanchez CE, Richards JE, Almli CR. Age-specific MRI templates for pediatric neuroimaging. Dev Neuropsychol 2012; 37: 379–399.
[53] Bhalerao GV, Parlikar R, Agrawal R, et al. Construction of population-specific Indian MRI brain template: Morphometric comparison with Chinese and Caucasian templates. Asian J Psychiatr 2018; 35: 93–100.
[54] Diedrichsen J, Balsters JH, Flavell J, et al. A probabilistic MR atlas of the human cerebellum. Neuroimage 2009; 46: 39–46.
[55] Hartley AA, Speer NK. Locating and fractionating working memory using functional neuroimaging: Storage, maintenance, and executive functions. Microsc Res Tech 2000; 51: 45–53.
[56] Cavanna AE, Trimble MR. The precuneus: a review of its functional anatomy and behavioural correlates. Brain 2006; 129: 564–583.
[57] Daselaar SM, Rice HJ, Greenberg DL, et al. The Spatiotemporal Dynamics of Autobiographical Memory: Neural Correlates of Recall, Emotional Intensity, and Reliving. Cereb Cortex 2008; 18: 217–229.
[58] Raz N, Levin N. Cortical and white matter mapping in the visual system-more than meets the eye: on the importance of functional imaging to understand visual system pathologies. Front Integr Neurosci 2014; 8: 1–11.
[59] Kirschen MP, Chen SHA, Schraedley-Desmond P, et al. Load- and practice-dependent increases in cerebro-cerebellar activation in verbal working memory: an fMRI study. Neuroimage 2005; 24: 462–472.
[60] Petacchi A, Laird AR, Fox PT, et al. Cerebellum and auditory function: An ALE meta-analysis of functional neuroimaging studies. Hum Brain Mapp 2005; 25: 118–128.
[61] Leung AWS, Alain C. Working memory load modulates the auditory “What” and “Where” neural networks. Neuroimage 2011; 55: 1260–1269.
[62] Fegen D, Buchsbaum BR, D’Esposito M. The effect of rehearsal rate and memory load on verbal working memory. Neuroimage 2015; 105: 120–131.
[63] Gould RL, Brown RG, Owen AM, et al. FMRI BOLD response to increasing task difficulty during successful paired associates learning. Neuroimage 2003; 20: 1006–1019.
[64] Leung H-C, Seelig D, C Gore J. The effect of memory load on cortical activity in the spatial working memory circuit. 2005. Epub ahead of print 1 January 2005. DOI: 10.3758/CABN.4.4.553.
[65] Borsook D, Maleki N, Burstein R. Chapter 42 - Migraine. In: Zigmond MJ, Rowland LP, Coyle JTBT-N of BD (eds). San Diego: Academic Press, pp. 693–708.
[66] Schott B, Wüstenberg T, Wimber M, et al. The relationship between level of processing and hippocampal-cortical functional connectivity during episodic memory formation in humans. Hum Brain Mapp; 34. Epub ahead of print 1 February 2013. DOI: 10.1002/hbm.21435.
[67] Rissman J, Gazzaley A, D’Esposito M. Dynamic adjustments in prefrontal, hippocampal, and inferior temporal interactions with increasing visual working memory load. Cereb Cortex 2008; 18: 1618–1629.
[68] Tapp E, Huxley M. The histological appearance of the human pineal gland from puberty to old age. J Pathol 1972; 108: 137–144.
[69] Bumb JM, Brockmann MA, Groden C, et al. Microstructural analysis of pineal volume using trueFISP imaging. World J Radiol 2013; 5: 166–172.
[70] Axelrod J, Wurtman RJ, Snyder SH. Control of Hydroxyindole O-Methyltransferase Activity in the Rat Pineal Gland by Environmental Lighting. J Biol Chem 1965; 240: 949–954.
[71] Tsivilis D, Vann SD, Denby C, et al. A disproportionate role for the fornix and mammillary bodies in recall versus recognition memory. Nat Neurosci 2008; 11: 834–842.
[72] Liebrich L, Schredl M, Findeisen P, et al. Morphology and Function: MR Pineal Volume and Melatonin Level in Human Saliva Are Correlated. J Magn Reson Imaging; 40. Epub ahead of print 1 October 2014. DOI: 10.1002/jmri.24449.
[73] Karatsoreos I. Links between Circadian Rhythms and Psychiatric Disease. Front Behav Neurosci 2014; 8: 162.
[74] Takahashi T, Nakamura M, Sasabayashi D, et al. Reduced pineal gland volume across the stages of schizophrenia. Schizophr Res 2019; 206: 163–170.
[75] De Nadai A, Storch E, Alvaro J. Development of Obsessive-Compulsive Disorder Following a Pineal Germinoma: A Case Report. Am J Psychiatry 2011; 168: 550; author reply 550-1.
[76] Mittal V, Karlsgodt K, Zinberg J, et al. Identification and Treatment of a Pineal Region Tumor in an Adolescent With Prodromal Psychotic Symptoms. Am J Psychiatry 2010; 167: 1033–1037.
[77] Hallam K, Olver J, Chambers V, et al. The heritability of melatonin sensitivity to bright nocturnal light in twins. Psychoneuroendocrinology 2006; 31: 867–875.
[78] Stein R, Kang H, McCorvy J, et al. Virtual discovery of melatonin receptor ligands to modulate circadian rhythms. Nature 2020; 579: 1–8.
[79] hosseini leila, Farokhi-Sisakht F, Badalzadeh R, et al. Nicotinamide Mononucleotide and Melatonin Alleviate Aging-induced Cognitive Impairment via Modulation of Mitochondrial Function and Apoptosis in the Prefrontal Cortex and Hippocampus. Neuroscience; 423. Epub ahead of print 1 October 2019. DOI: 10.1016/j.neuroscience.2019.09.037.
[80] Lee TYC, Curtin J. The effects of melatonin prophylaxis on sensory recovery and postoperative pain following orthognathic surgery: a triple-blind randomized controlled trial and biochemical analysis. Int J Oral Maxillofac Surg; 49. Epub ahead of print 1 August 2019. DOI: 10.1016/j.ijom.2019.07.006.
[81] Aubin S, Kupers R, Ptito M, et al. Melatonin and cortisol profiles in the absence of light perception. Behav Brain Res; 317. Epub ahead of print 15 January 2017. DOI: 10.1016/j.bbr.2016.09.060.
[82] Ghaziuddin N, Shamseddeen W, Bertram H, et al. Salivary Melatonin Onset in Youth at Familial Risk for Bipolar Disorder. Psychiatry Res; 274. Epub ahead of print 1 February 2019. DOI: 10.1016/j.psychres.2019.02.013.
[83] Yun A, Bazar K, Lee P. Pineal attrition, loss of cognitive plasticity, and onset of puberty during the teen years: Is it a modern maladaptation exposed by evolutionary displacement? Med Hypotheses 2004; 63: 939–950.
[84] Wu Y-H, Swaab D. The human pineal gland and melatonin in aging and Alzheimer’s disease. J Pineal Res 2005; 38: 145–152.
[85] Zhou J-N, Liu R-Y, Kamphorst W, et al. Early neuropathological Alzheimer’s changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J Pineal Res 2003; 35: 125–130.
[86] Sahbaz C, Özer O, Kurtulmus A, et al. Evidence for an association of serum melatonin concentrations with recognition and circadian preferences in patients with schizophrenia. Metab Brain Dis; 34. Epub ahead of print 13 February 2019. DOI: 10.1007/s11011-019-00395-3.
[87] Sluimer J, Flier W, Karas G, et al. Whole-Brain Atrophy Rate and Cognitive Decline: Longitudinal MR Study of Memory Clinic Patients 1. Radiology 2008; 248: 590–598.
[88] Mcdaniel M. Big-brained people are smarter: A meta-analysis of the relationship between in vivo brain volume and intelligence. Intelligence 2005; 33: 337–346.
[89] Rushton J, Ankney C. Whole Brain Size and General Mental Ability: A Review. Int J Neurosci 2009; 119: 691–731.
[90] Ramanoel S, Hoyau E, Kauffmann L, et al. Gray Matter Volume and Cognitive Performance During Normal Aging. A Voxel-Based Morphometry Study. Front Aging Neurosci; 10. Epub ahead of print 1 July 2018. DOI: 10.3389/fnagi.2018.00235.
[91] Rao S, Martin A, Huelin R, et al. Correlations between MRI and Information Processing Speed in MS: A Meta-Analysis. Mult Scler Int 2014; 2014: 975803.
[92] MacPherson S, Cox S, Dickie D, et al. Processing speed and the relationship between Trail Making Test-B performance, cortical thinning and white matter microstructure in older adults. Cortex; 95. Epub ahead of print 1 August 2017. DOI: 10.1016/j.cortex.2017.07.021.
[93] Karnath H-O. New insights into the functions of the superior temporal cortex. Nat Rev Neurosci 2001; 2: 568–576.
[94] Karnath H-O. The subcortical anatomy of human spatial neglect: putamen, caudate nucleus and pulvinar. Brain 2002; 125: 350–360.
[95] Takeuchi H, Taki Y, Sassa Y, et al. Regional gray and white matter volume associated with Stroop interference: Evidence from voxel-based morphometry. Neuroimage 2012; 59: 2899–2907.
[96] Batouli SAH, Sachdev PS, Wen W, et al. Heritability of brain volumes in older adults: the Older Australian Twins Study. Neurobiol Aging 2014; 35: 937.e5-937.e18.
[97] Lissoni P, Messina G, Porro G, et al. A review on the cognitive functions of basal ganglia, amygdala, hippocampus, habenula, nucleus accumbens, cerebellum, and pineal gland. Ment Heal Addict Res; 5. Epub ahead of print 2020. DOI: 10.15761/MHAR.1000190.
[98] Brzezinski A. Melatonin in Humans. N Engl J Med 1997; 336: 186–195.
[99] Bob P, Fedor-Freybergh P. Melatonin, consciousness, and traumatic stress. J Pineal Res 2008; 44: 341–347.
[100] Aranarochana A, Chaisawang P, Sirichoat A, et al. Protective effects of melatonin against valproic acid-induced memory impairments and reductions in adult rat hippocampal neurogenesis. Neuroscience 2019; 406: 580–593.
[101] Sirichoat A, Krutsri S, Suwannakot K, et al. Melatonin protects against methotrexate-induced memory deficit and hippocampal neurogenesis impairment in a rat model. Biochem Pharmacol 2019; 163: 225–233.
[102] Bagheri S, Moradi K, Ehghaghi E, et al. Melatonin improves learning and memory of mice with chronic social isolation stress via an interaction between microglia polarization and BDNF/TrkB/CREB signaling pathway. Eur J Pharmacol 2021; 908: 174358.
[103] Alzoubi KH, Mayyas FA, Mahafzah R, et al. Melatonin prevents memory impairment induced by high-fat diet: Role of oxidative stress. Behav Brain Res 2018; 336: 93–98.
[104] Saxena G, Bharti S, Kamat PK, et al. Melatonin alleviates memory deficits and neuronal degeneration induced by intracerebroventricular administration of streptozotocin in rats. Pharmacol Biochem Behav 2010; 94: 397–403.
[105] Teyler TJ, Rudy JW. The hippocampal indexing theory and episodic memory: Updating the index. Hippocampus 2007; 17: 1158–1169.
[106] Santini E, Huynh TN, Klann E. Mechanisms of translation control underlying long-lasting synaptic plasticity and the consolidation of long-term memory. 1st ed. Elsevier Inc. Epub ahead of print 2014. DOI: 10.1016/B978-0-12-420170-5.00005-2.
[107] Schwartz BL. Memory and the Brain. In: FOUNDATIONS AND APPLICATIONS. SAGE Publications Inc., 2014, pp. 29–58.
[108] Lashley KS. IN SEARCH OF THE ENGRAM. Soc Exp Biol, Symp 1950; 4: 454–482.
[109] Scoville WB, Milner B. LOSS OF RECENT MEMORY AFTER BILATERAL HIPPOCAMPAL LESIONS. J Neurol Neurosurg Psychiatry 1957; 20: 11–21.
[110] O’Keefe J, Dostrovsky J. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Res 1971; 34: 171–175.
[111] Engert F, Bonhoeffer T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 1999; 399: 66–70.
[112] Pastalkova E, Serrano P, Pinkhasova D, et al. Storage of Spatial Information by the Maintenance Mechanism of LTP. Science (80- ) 2006; 313: 1141 LP – 1144.
[113] Day JJ, Sweatt JD. Epigenetic mechanisms in cognition. Neuron 2011; 70: 813–829.
[114] Tonegawa S, Pignatelli M, Roy DS, et al. Memory engram storage and retrieval. Curr Opin Neurobiol 2015; 35: 101–109.
Files
IssueVol 11 No 4 (2024) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/fbt.v11i4.16501
Keywords
Pineal Gland Cognition Magnetic Resonance Imaging Memory Brain Volume functional Magnetic Resonance Imaging

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Sisakhti M, Batouli SAH. Possible Role of the Pineal Gland in the Human Memory System. Frontiers Biomed Technol. 2024;11(4):530-547.